BackgroundSince 2015, mechanical thrombectomy has been the standard treatment for emergent large vessel occlusion ischemic stroke.ObjectiveTo investigate, using the previously published Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683), how the protein expression of a patient’s intracranial blood during ischemic stroke compares with the protein expression of their systemic arterial blood in order to better understand and treat stroke.MethodsPlasma samples from 25 subjects underwent proteomic analysis, where intracranial protein expression was compared with systemic protein levels. Data including sex, comorbidities, infarct volume, and infarct time were included for each subject.ResultsA majority of important proteins had a lower expression in intracranial blood than in systemic arterial blood. Proteins with the most significant changes in expression were: endopeptidase at −0.26 (p<0.0001), phospholipid transfer protein (PLTP) at −0.26 (p=0.0005), uromodulin (UMOD) at −0.14 (p=0.002), ficolin-2 (FCN2) at −0.46 (p=0.005), C-C motif chemokine 19 (CCL19) at −0.51 (p<0.0001), C-C motif chemokine 20 (CCL20) at −0.40 (p<0.0001), fibroblast growth factor 21 at −0.37 (p=0.0002), and C-C motif chemokine (CCL23) at −0.43 (p=0.0003).ConclusionsEvaluation of proteomic changes in the intravascular space of a cerebral infarct in progress in human subjects suggested that changes in proteins such PLTP, fetuin-B (FETUB), and FCN2 may be involved in atherosclerotic changes, and chemokines such as CCL23 are known to play a role in the Th2 autoimmune response. These data provide a scientific springboard for identifying clinically relevant biomarkers for diagnosis/prognosis, and targets for much needed neuroprotective/neuroreparative pharmacotherapies.

Background Emergent large vessel occlusion (ELVO) strokes are devastating ischemic vascular events for which novel treatment options are needed. Using vascular cell adhesion molecule 1 (VCAM1) as a prototype, the objective of this study was to identify proteomic biomarkers and network signaling functions that are potential therapeutic targets for adjuvant treatment for mechanical thrombectomy. Methods The blood and clot thrombectomy and collaboration (BACTRAC) study is a continually enrolling tissue bank and registry from stroke patients undergoing mechanical thrombectomy. Plasma proteins from intracranial (distal to clot) and systemic arterial blood (carotid) were analyzed by Olink Proteomics for N=42 subjects. Statistical analysis of plasma proteomics used independent sample t tests, correlations, linear regression, and robust regression models to determine network signaling and predictors of clinical outcomes. Data and network analyses were performed using IBM SPSS Statistics, SAS v 9.4, and STRING V11. Results Increased systemic (p<0.001) and intracranial (p=0.013) levels of VCAM1 were associated with the presence of hypertension. Intracranial VCAM1 was positively correlated to both infarct volume (p=0.032; r=0.34) and edema volume (p=0.026; r=0.35). The %∆ in NIHSS from admittance to discharge was found to be significantly correlated to both systemic (p=0.013; r = −0.409) and intracranial (p=0.011; r = −0.421) VCAM1 levels indicating elevated levels of systemic and intracranial VCAM1 are associated with reduced improvement of stroke severity based on NIHSS from admittance to discharge. STRING-generated analyses identified biologic functional descriptions as well as function-associated proteins from the predictive models of infarct and edema volume. Conclusions The current study provides novel data on systemic and intracranial VCAM1 in relation to stroke comorbidities, stroke severity, functional outcomes, and the role VCAM1 plays in complex protein-protein signaling pathways. These data will allow future studies to develop predictive biomarkers and proteomic targets for drug development to improve our ability to treat a devastating pathology.

Regenerating Family Member 3 Alpha (REG3A) is a multifunctional protein with antimicrobial activity, and primarily secreted by the intestine and pancreas. Studies have shown an increased expression of REG3A in systemic inflammatory responses to acute injury and infection, but studies investigating REG3A during the pathogenesis of ischemic stroke are limited. The aims of this study were to examine the associations between arterial expression of REG3A and other arterial inflammatory proteins implicated in stroke pathogenesis, as well as associations between REG3A and markers of poor outcome for ischemic stroke. The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes thrombectomy to isolate intracranial arterial blood (i.e. distal to thrombus) and systemic arterial blood (i.e. carotid). Samples were analyzed by Olink Proteomics for N = 42 subjects. Statistical analyses of plasma proteins included 2‐sample t‐tests, spearman and biserial correlations, and robust regression models to elucidate network signaling and association to clinical outcomes. Results indicated that levels of systemic REG3A were positively correlated with inflammatory proteins interleukin IL6 (R = 0.344, p = 0.030) and IL17C (R = 0.468, p = 0.002). 2‐sided t‐ tests examining differences of systemic REG3A within quartiles of NIHSS admission score depicted significant differences between quartiles. Those with NIHSS scores corresponding to moderate and moderate‐severe neurofunctional deficits had significantly higher levels of systemic REG3A compared to those with NIHSS scores corresponding to mild and mild‐moderate neurofunctional deficits (p = 0.016). STRING analyses of proteins in each robust regression model demonstrated substantial networking between REG3A and other systemic proteins highly relevant to ischemic stroke. The present study provides novel data on systemic REG3A in the context of ischemic stroke. These results demonstrate the influential role of REG3A regarding surrogate functional and radiographic outcomes of stroke severity. Additionally, they provide novel insight into the role of REG3A and related proteins during the complex neuroinflammatory process of ischemic stroke. These data provide a foundation for future studies to investigate REG3A and related networking proteins as potential biomarkers with prognostic potential, as well as potential therapeutic targets.

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OBJECTIVE In the absence of clear guidelines and consistent natural history data, the decision to treat unruptured intracranial aneurysms (UIAs) is a matter of some controversy. Currently, decisions are often guided by a consensus of cerebrovascular specialist teams and patient preferences. It is unclear how paradigm-shifting developments in the detection and treatment of UIAs have affected the size of the UIAs that are selected for treatment. Herein, the authors aimed to study potential changes in the average size of the UIAs that were treated over time. They hypothesized that the average size of UIAs that are treated is decreasing over time. METHODS A systematic search of the literature was performed to identify all studies describing the size of UIAs that were treated using any modality. Scatter diagrams with trend lines were used to plot the size of the aneurysms treated over time and assess for the presence of a potentially significant trend via statistical correlation tests. Subgroup analyses based on type of treatment, country of study, and specialty of the authors were performed. RESULTS A total of 240 studies including 35,150 UIAs treated between 1987 and 2021 met all eligibility criteria and were entered in the analysis. The mean age of patients was 55.5 years, and 70.7% of the patients were females. There was a significant decrease in the size of treated UIAs over time (Spearman’s r = −0.186, p < 0.001), with a 0.71-mm decrease in the average size of treated UIAs every 5 years since 1987 and an annual mean dropping below 7 mm in 2012. This decreasing trend was present in surgically and endovascularly treated UIAs (p < 0.001 for both), in more developed and developing countries (p < 0.001 for both), within neurosurgical and non-neurosurgical specialties (p < 0.001 for both), most prominently in the US (Spearman’s r = −0.482, p < 0.001), and less prominently in Europe (Spearman’s r = −0.221, p < 0.001) and was not detected in East Asia. CONCLUSIONS The present study indicates that based on the treated UIA size data published in the literature over the past 35 years, smaller UIAs are being treated over time. This trend is likely driven by safer treatments. However, future studies should elucidate the cost-effectiveness of treating smaller UIAs as well as the possible real-world contribution of this trend in preventing aneurysmal subarachnoid hemorrhage.

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